Bortezomib (Btz, VELCADE) is a FDA approved drug for the treatment of patients with multiple myeloma or mantle cell lymphoma who are resistant to other drugs. Mouse studies indicate that Btz is also a bone anabolic agent. However, serious side effects of Btz, such as peripheral neuropathy and thrombocytopenia, limit its clinical utilization. The goal of this application is to generate bone-targeted Btz conjugates and test thei bioactivities. This will be carried out by a new interdisciplinary team including a Bone Biologist (Xing) and Chemist (Boeckman). Two special aims are proposed. In Aim 1, bone-targeted Btz conjugates will be designed and synthesized by conjugating Btz to a bisphosphonate (BP) residue using novel chemical linkers to generate BP-Btz conjugates (1A). If BP-Btz conjugates bind to bone matrix and inhibit osteoclast function will be examined in vitro using bone slices that have been pre-incubated with BP-Btz. The effects of BP-Btz conjugates on osteoblast differentiation will be examined (1B). In Aim 2, the effects of BP-Btz conjugates on OVX-induced bone loss (2A) and aged related fracture nonunion (2B) will be examined in mouse models. The side effects of BP-Btz will be compared to those of Btz. The preliminary data indicated that our recently generated BP-Btz1 binds to bone slices and maintains its bioactivity of osteoclast inhibition and osteoblast stimulation in vitro, supporting the feasibility of the proposal. The application fits the R21 mechanism in 2 ways: 1) it is high risk because it is not known if our BP-Btz conjugates are functional in vivo and if they have lesser systemic adverse effects as expected; 2) it is highly reward because BP-Btz conjugates are proven working in vivo, it will have significant impact not only on patient treatment, but also on synthesizing other bone-targeted drugs using the new conjugation technology. Furthermore, this application brings in 2 well-established investigators from different research fields to work on a very important problem that otherwise cannot be solved by individual PIs.